MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis
MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis
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DOI：
10.1172/jci73351
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发表时间：
2014-07-01
影响因子：
15.9
通讯作者：
Chang, Chun-Ju
中科院分区：
文献类型：
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作者：
Chao, Chi-Hong;Chang, Chao-Ching;Chang, Chun-Ju
表观遗传控制的失调与微环境刺激引起的肿瘤发生有关;然而，表观遗传功能障碍所涉及的调控途径在很大程度上尚不清楚。我们已经确定，一个关键的表观遗传调节因子，microRNA-205（miR-205），被抑制的配体锯齿1，这是从肿瘤间质分泌，以促进癌症相关的干细胞表型。乳腺上皮细胞中miR-205的敲低促进上皮-间充质转化（EMT），破坏上皮细胞极性，并增强对称分裂以扩增干细胞群体。此外，miR-205缺陷小鼠自发地发展出乳腺病变，而miR-205的激活显著降低了乳腺癌的干性。这些数据提供了证据，将肿瘤微环境和microRNA依赖性调节与上皮极性破坏和异常乳腺干细胞分裂联系起来，这反过来又导致干细胞群的扩增和肿瘤发生。这项研究阐明了miR-205在调节乳腺干细胞命运中的重要作用，表明了限制乳腺癌发生的潜在治疗靶点。
Dysregulation of epigenetic controls is associated with tumorigenesis in response to microenvironmental stimuli; however, the regulatory pathways involved in epigenetic dysfunction are largely unclear. We have determined that a critical epigenetic regulator, microRNA-205 (miR-205), is repressed by the ligand jagged1, which is secreted from the tumor stroma to promote a cancer-associated stem cell phenotype. Knockdown of miR-205 in mammary epithelial cells promoted epithelial-mesenchymal transition (EMT), disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, miR-205-deficient mice spontaneously developed mammary lesions, while activation of miR-205 markedly diminished breast cancer sternness. These data provide evidence that links tumor microenvironment and microRNA-dependent regulation to disruption of epithelial polarity and aberrant mammary stem cell division, which in turn leads to an expansion of stem cell population and tumorigenesis. This study elucidates an important role for miR-205 in the regulation of mammary stem cell fate, suggesting a potential therapeutic target for limiting breast cancer genesis.